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PNAS 98 (20): 11598-11603

Copyright © 2001 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / MEDICAL SCIENCES

A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus

Lindsey D. Mayo David B. Donner*

Department of Microbiology and Immunology, Indiana University School of Medicine, and the Walther Oncology Center, Indianapolis, IN 46202

Received for publication April 11, 2001.

Abstract: The Mdm2 oncoprotein promotes cell survival and cell cycle progression by inhibiting the p53 tumor suppressor protein. To regulate p53, Mdm2 must gain nuclear entry, and the mechanism that induces this is now identified. Mitogen-induced activation of phosphatidylinositol 3-kinase (PI3-kinase) and its downstream target, the Akt/PKB serine-threonine kinase, results in phosphorylation of Mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of Mdm2 from the cytoplasm into the nucleus. Pharmacological blockade of PI3-kinase/Akt signaling or expression of dominant-negative PI3-kinase or Akt inhibits nuclear entry of Mdm2, increases cellular levels of p53, and augments p53 transcriptional activity. Expression of constitutively active Akt promotes nuclear entry of Mdm2, diminishes cellular levels of p53, and decreases p53 transcriptional activity. Mutation of the Akt phosphorylation sites in Mdm2 produces a mutant protein that is unable to enter the nucleus and increases p53 activity. The demonstration that PI3-kinase/Akt signaling affects Mdm2 localization provides insight into how this pathway, which is inappropriately activated in many malignancies, affects the function of p53.


* To whom reprint requests should be addressed at: The Walther Oncology Center, Indiana University School of Medicine, 1044 West Walnut Street, Indianapolis, IN 46202. E-mail: ddonner{at}IUPUI.edu.

Edited by Pedro M. Cuatrecasas, University of California at San Diego, School of Medicine, Rancho Santa Fe, CA, and approved July 3, 2001

This paper was submitted directly (Track II) to the PNAS office.

See commentary on page 10983.

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Mitogen-Activated Protein Kinase Kinase Inhibition Enhances Nuclear Proapoptotic Function of p53 in Acute Myelogenous Leukemia Cells.
K. Kojima, M. Konopleva, I. J. Samudio, V. Ruvolo, and M. Andreeff (2007)
Cancer Res. 67, 3210-3219
   Abstract »    Full Text »    PDF »
MDM2 Splice Variants Predominantly Localize to the Nucleoplasm Mediated by a COOH-Terminal Nuclear Localization Signal.
K. Schuster, L. Fan, and L. C. Harris (2007)
Mol. Cancer Res. 5, 403-412
   Abstract »    Full Text »    PDF »
Met acts on Mdm2 via mTOR to signal cell survival during development.
A. Moumen, S. Patane, A. Porras, R. Dono, and F. Maina (2007)
Development 134, 1443-1451
   Abstract »    Full Text »    PDF »
Twist Transcriptionally Up-regulates AKT2 in Breast Cancer Cells Leading to Increased Migration, Invasion, and Resistance to Paclitaxel.
G. Z. Cheng, J. Chan, Q. Wang, W. Zhang, C. D. Sun, and L.-H. Wang (2007)
Cancer Res. 67, 1979-1987
   Abstract »    Full Text »    PDF »
Curcumin, a Dietary Component, Has Anticancer, Chemosensitization, and Radiosensitization Effects by Down-regulating the MDM2 Oncogene through the PI3K/mTOR/ETS2 Pathway.
M. Li, Z. Zhang, D. L. Hill, H. Wang, and R. Zhang (2007)
Cancer Res. 67, 1988-1996
   Abstract »    Full Text »    PDF »
The Akt inhibitor deguelin, is an angiopreventive agent also acting on the NF-{kappa}B pathway.
R. Dell'Eva, C. Ambrosini, S. Minghelli, D. M. Noonan, A. Albini, and N. Ferrari (2007)
Carcinogenesis 28, 404-413
   Abstract »    Full Text »    PDF »
MEK-ERK-mediated Phosphorylation of Mdm2 at Ser-166 in Hepatocytes: Mdm2 IS ACTIVATED IN RESPONSE TO INHIBITED Akt SIGNALING.
M. Malmlof, E. Roudier, J. Hogberg, and U. Stenius (2007)
J. Biol. Chem. 282, 2288-2296
   Abstract »    Full Text »    PDF »
Nutlin3 Blocks Vascular Endothelial Growth Factor Induction by Preventing the Interaction between Hypoxia Inducible Factor 1{alpha} and Hdm2.
G. A. LaRusch, M. W. Jackson, J. D. Dunbar, R. S. Warren, D. B. Donner, and L. D. Mayo (2007)
Cancer Res. 67, 450-454
   Abstract »    Full Text »    PDF »
Activation of p53-Dependent Growth Suppression in Human Cells by Mutations in PTEN or PIK3CA.
J.-S. Kim, C. Lee, C. L. Bonifant, H. Ressom, and T. Waldman (2007)
Mol. Cell. Biol. 27, 662-677
   Abstract »    Full Text »    PDF »
Human MDM2 Isoforms Translated Differentially on Constitutive versus p53-Regulated Transcripts Have Distinct Functions in the p53/MDM2 and TSG101/MDM2 Feedback Control Loops.
T.-H. Cheng and S. N. Cohen (2007)
Mol. Cell. Biol. 27, 111-119
   Abstract »    Full Text »    PDF »
MDM2 Is Required for Suppression of Apoptosis by Activated Akt1 in Salivary Acinar Cells.
K. H. Limesand, K. L. Schwertfeger, and S. M. Anderson (2006)
Mol. Cell. Biol. 26, 8840-8856
   Abstract »    Full Text »    PDF »
Regulation of the Ring Finger E3 Ligase Siah2 by p38 MAPK.
A. Khurana, K. Nakayama, S. Williams, R. J. Davis, T. Mustelin, and Z. Ronai (2006)
J. Biol. Chem. 281, 35316-35326
   Abstract »    Full Text »    PDF »
Statins induce mammalian target of rapamycin (mTOR)-mediated inhibition of Akt signaling and sensitize p53-deficient cells to cytostatic drugs..
E. Roudier, O. Mistafa, and U. Stenius (2006)
Mol. Cancer Ther. 5, 2706-2715
   Abstract »    Full Text »    PDF »
PYK2 mediates anti-apoptotic AKT signaling in response to benzo[a]pyrene diol epoxide in mammary epithelial cells.
A. D. Burdick, I. D. Ivnitski-Steele, F. T. Lauer, and S. W. Burchiel (2006)
Carcinogenesis 27, 2331-2340
   Abstract »    Full Text »    PDF »

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